Parenteral depot systems are widely known to those skilled in the art and are well accepted concepts for long term delivery of drugs. These systems are based on biodegradable polymer systems or lipid formulations, e.g. oil solutions and oil suspensions. However, both systems show a serious disadvantage since, after the drug release process has terminated, the lipids or polymer carriers are still at the injection site for a long period of time and, for some systems such as implants, they may even have to be eliminated by surgery. Furthermore, the application of either oils or biodegradable polymers such as polylactic/polyglycolic acid show limited applications since each concept requires specific physicochemical properties of the bioactive material to be included into the systems, e.g. solubility or stability/compatibility.
Hence, parenteral therapy needs a delivery system for bioactive materials applicable for both highly polar as well as nonpolar bioactive materials for which the delivery system shows an intrinsic rate controlling mechanism for drug release, which can be varied over an extensive time frame. A characteristic for such delivery system should be that both the drug release and the biodegradation occur simultaneously.
Since parenteral administration of bioactive materials often needs to be carried out by physicians or nurses and the fact that many people find such therapy uncomfortable, a lot of effort is made on developing drug delivery forms applicable for other routes of administration. Still, the most common route of administration is the enteral (oral, rectal) but during the past decade several attempts have been made to develop intranasal or transdermal delivery systems as alternatives to the parenteral route.
However, the adsorption through biological membranes is a very complex process due to the varying nature of the different membranes to be bypassed as well as the varying nature of the bioactive material used. Many enterally administered drugs also show a high biotransformation when absorbed from the gastrointestinal tract or show a restricted or erratic absorption capacity due to their physicochemical properties, molecular size or sensitivity to degradation processes in the gut, or due to some specific absorption mechanism in limited parts of the gastrointestinal tract. Also, bioactive material administered intranasally or dermally may show erratic and irregular absorption and many delivery formulations hence need the addition of absorption enhancers which in some cases have been shown to be detrimental to the nasal mucosa or the skin due to local side effects.
Due to this lack of regularity, the enteral/nasal/dermal therapy needs a delivery system which eliminates this variability and which is sufficiently flexible for incorporating a variety of bioactive materials, independent of their physicochemical properties, molecular size or source of origin, particularly for such bioactive materials which currently cannot be administered via the enteral route due to limited absorption capacity.
Several papers have been published demonstrating the influence of lipids on drug absorption. However, various results have been obtained showing an enhanced oral absorption either in man or animals, for example:
griseofulvin in an oil-in-water emulsion (Bates and Sequeria, J. Pharm. Sci., 1975, 64, 793), PA1 cefoxitin in an oil-in-water emulsion (Palin et al., Int. J. Pharm. 1986, 33, 99), PA1 insulin in liposomes of phosphatidylcholine/cholesterol, as well as in water-in-oil microemulsion (Patel and Ryman, FEBS Letters, 1976, 62, 60; Cho and Flynn, Lancet, 1989, Dec. 23/30), PA1 cyclosporine in microemulsion (Tarr and Yalkowsky, Pharm. Res. 1989, 6, 4), PA1 enhanced nasal absorption in rats of insulin in solution with lysophosphatidylcholine (Illum et al., lnt. J. Pharm., 1989, 57, 49).
Decreased absorption was found for propranolol in coconut oil (Palin et al., J. Pharm. Pharmacol., 1989, 41, 579) or no effect at all for vitamin K incorporated into mixed micelles based upon glycolate and lecithin (Winn et al., J. Pharm. Pharmacol., 1989, 41, 257). Furthermore, Rowland and Woodley (Biochim. Biophys. Acta, 1980, 620, 400) have shown that many liposomal systems are quite unstable in the gastrointestinal tract and that drugs incorporated into liposomes gave the same absorption compared to free drug per se. It has recently been indicated in thermodynamic studies, that human insulin-DEAE-dextran complex entrapped in liposomes may present a more stable system than the uncomplexed and/or unentrapped human insulin. However, no evidence that this really works in vivo have been shown (Manosroi et al., Drug Dev. Ind. Pharm., 1990, 16,837).
In some cases there is a therapeutic need to administer bioactive materials locally, such as in wounds after surgery or for the treatment of burns. In those cases, a need exists to deliver the bioactive material locally as well as for an extended period of time in a controllable manner since after surgery no further administration of the formulation is possible, and as in the case of burn injuries, pain may cause severe discomfort to the patient upon repeated administrations. Furthermore, local application to other regions in the body, such as in the vagina, with an extended drug delivery may show therapeutic advantages.
It is well known to those skilled in the art that bioactive materials can be entrapped into unique lipid/aqueous spherical structures defined as liposomes. A liposome is defined as a structure consisting of one or more concentric spheres of lipid bilayers separated by water or aqueous buffer compartments. Thus far, liposome formation and hence manufacturing, has been restricted to techniques where the said formation is carried out in vitro.
Numerous patents and scientific papers on liposomes have been published and the technical field of applying various lipid derivatives in combination with amphiphatic compounds such as phospholipids are well known to those skilled in the art. Liposomes can be prepared by different methods using solvents, reduced pressure, two-phase systems, freeze drying, sonication etc. (Weiner et al., Drug Dev. Ind. Pharm. 1989, 15, 1523).The process technology assigned to these methods is highly complicated. Due to the specific demand in terms of the physicochemical properties of the drug molecule in order to form stable liposome structures, only a limited number of candidate drugs have been shown to be applicable in liposomes formed in vitro. The major application of liposomes have so far been restricted to parenteral delivery and for cosmetic skin care products even though attempts have been made for other routes of administration such as oral, nasal, pulmonary. The applications for parenteral use have been focused on intravenous administration and drug targeting and to some minor extent for extended or controlled release from a depot. Thus far, the applications of liposomes are restricted to the formation and incorporation of bioactive materials in vitro.
A composition for oral delivery of drugs has been disclosed in a patent by Yesair (WO 86/05694), comprising non-esterified fatty acids, monoglycerides with fatty acids having 14-18 carbon atoms, lysophosphatidylcholine in which the fatty acid component has 14-18 carbon atoms and a drug. None Of these single-chained components are bilayer-forming which is a prerequisite for at least one of the lipid components in the present invention.
U.S. Pat. No. 4,610,888 discloses a way of producing liposomes where water-soluble compounds are incorporated. However, this patent deals with globular structures present from the beginning, in contrast to the present invention. The said invention also uses organic solvents in the process which is in contrast to the present invention where the Biosomes are formed spontaneously without any chemical or physical treatment or initiation.
Other documents disclosing the preparation of liposomes are EP 158 441, EP 260 241 and WO 87/07502. According to EP 158 441, in contrast to the present invention, at least one water-miscible liquid (e.g. glycerol, ethanol) and 5-40% water should be added to at least one membrane lipid (e.g. phospholipids such as soy lecithin and egg yolk lecithin. EP 260 241 discloses a dry lipid-based solid material which forms or reconstitutes liposomes in the presence of water. This composition should be dehydrated, e.g. through lyophilization or spray-drying which should not destroy the liposome structure. The liposome structure is thus present from the beginning, in contrast to the present invention. WO 87/07502 discloses a pro-liposome formulation comprising at least one volatile liquid propellant and at least one lipid component. Also in this case discrete particles are formed by dehydration and thus the liposomes are present from the beginning.
The current well known liposome technology, where the systems are prepared in vitro before administration, suffers from the disadvantage that the systems are quite unstable and factors such as temperature or other constituents present in the formulation may dramatically change the nature of the liposomes by irreversibly damaging the bilayers. It is also well known (see Weiner above) that liposomes composed of crude egg yolk phosphatides are not physically stable in vitro at ambient temperatures for more than a few months which limits the application of these formulations in routine practice. By applying the matrix according to the invention the above mentioned stability problems can be avoided.
The above mentioned problems and needs can be met by using a delivery system as described in this application. The present invention, relating to Biosome formation in vivo, will show advantages as compared to already well known lipid drug delivery systems.
The present invention discloses a way to produce, use and/or utilize an entrapment or adsorption procedure for bioactive substances into unique lipid matrices. Such a combination may be used as a pharmaceutical formulation within human and veterinary medicine, in agriculture, or as cosmetic or food/nutritional formulations.